Thyroglobulin:
New Guidelines for Testing in Posttreatment Patients

Introduction
Thyroid cancer is considered to be one of the most "curable" cancers. Thyroid tumors that are detected and removed while small (less than 1.5 cm in diameter) have the best prognosis; detection of metastasis bodes less favorably. Fortunately, distant metastasis is very uncommon, but tumors that invade or extend beyond the thyroid capsule have a worse prognosis because of a high recurrence rate after primary treatment.

For patients with low-risk well-differentiated thyroid cancers (WDTC), treatment involves near-total thyroidectomy and/or ¹³¹I ablation. This is followed by lifelong administration of thyroxine (T4) to replace endogenous sources and to suppress thyroid-stimulating hormone (TSH) production, as well as periodic monitoring of thyroglobulin (Tg) levels. Previously, it was thought that an undetectable Tg level while on T4 suppression signified clinical remission. However, recent studies have demonstrated that this criterion misses 20 to 25 percent of residual or metastatic disease.

The 2003 consensus report from the NACB published in the Journal of Clinical Endocrinology and Metabolism¹ describes a method of testing that improves the overall ability of Tg assays to detect residual or recurrent WDTC.

Monitoring low-risk WDTC patients with Tg
Tg determinations can be used alone or in conjunction with ¹³¹I whole body scans (WBS) to detect cancer recurrence. TSH stimulation, induced either through withdrawal of T4 suppression or by the intramuscular administration of recombinant human TSH (rhTSH), substantially improves the sensitivity of both WBS and Tg measurements.^2,3 Most endocrinologists who treat WDTC patients prefer to use rhTSH-stimulated Tg measurements because this approach obviates the 4 to 6 weeks needed to achieve full withdrawal from T4 replacement and avoids any of the unpleasant symptoms of hypothyroidism in their patients.

The NACB consensus report addresses the utility of rhTSH-stimulated Tg testing alone to monitor certain low-risk WDTC patients for recurrences. The report reviews recent data from eight published studies demonstrating that rhTSH-stimulated Tg testing is sufficiently sensitive to monitor most low-risk WDTC patients. The report also includes an algorithm with guidelines for detecting recurrent cancer in low-risk WDTC patients using rhTSH-stimulated Tg testing (Figure 1).

Figure 1. A suggested management algorithm for surveillance of low-risk WDTC patients for possible recurrence. (Adapted from reference 1.)

click image to enlarge

Meeting the Tg performance guidelines
In addition to supplying recommendations on testing for recurrence or metastasis, the NACB report also specifies the following minimum performance requirements for a Tg assay that is to be used as a monitoring method for low-risk patients with WDTC:

· A functional sensitivity of 1 ng/mL or better
· Standardization to the CRM-457 standard
· A lower limit of normal of approximately 3 ng/mL.

The IMMULITE^® family of Thyroglobulin assays meets these requirements according to DPC performance attributes.

The clinical utility of IMMULITE 2000 Tg has been documented in a recently peer-reviewed paper by Pacini et al.⁴ In this paper, the diagnostic accuracy of IMMULITE 2000 Thyroglobulin measurement and diagnostic WBS was reported, alone or in combination, after rhTSH stimulation in a retrospective, consecutive series of patients undergoing follow-up for WDTC. Routine procedures also included neck ultrasound in every patient and posttherapy WBS when indicated. The population included 340 consecutive patients with WDTC, previously treated with near-total thyroidectomy and ¹³¹I thyroid ablation. At baseline on thyroid suppression, 294 patients had undetectable (< 1 ng/mL) serum Tg and negative anti-Tg autoantibodies (TgAb), 25 patients had undetectable serum Tg and positive TgAb, and 21 patients had detectable serum Tg and negative TgAb. These patients were tested for the presence of active disease by rhTSH stimulation. A synopsis of the study results is presented in Table 1.

Table 1. The diagnostic sensitivity for detecting active disease and the negative predictive value (NPV) of different postsurgical monitoring methods (based on reference 4).

Pacini et al. concluded that the rhTSH-stimulated Tg test combined with neck ultrasonography has the highest diagnostic accuracy in detecting persistent disease in the follow-up of differentiated thyroid carcinoma. They believe that a detectable level of serum Tg during T4 suppression, its conversion from undetectable to detectable after rhTSH stimulation, and/or a suspicious finding at ultrasound can identify patients requiring therapeutic procedures without the need for diagnostic WBS.⁴ This obviates the need for WBS, thus minimizing additional use of ¹³¹I, to which long-term exposure has been associated with toxicity to other organs (mainly the salivary glands).

Conclusion
Early detection and treatment of recurrent thyroid cancer are important goals in improving long-term outcome. The most sensitive means to accomplish these objectives utilizes sensitive Tg measurements after rh-TSH stimulation, which has changed the strategy of follow-up while preserving the patient's quality of life.

IMMULITE/IMMULITE 1000 and IMMULITE 2000/2500 Tg assays all meet the NACB's performance requirements for functional sensitivity that is well below the lower limit of normal for these assays. These features provide both the laboratory and the clinician with assays suitable for detecting cancer recurrence in low-risk WDTC patients.

For a copy of DPC's new technical report, A New Paradigm of Thyroglobulin Testing for Recurrent Thyroid Cancer (catalog number: ZB236), please contact your DPC representative.